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ToxSci Advance Access published online on December 8, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn254
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Werner syndrome protein, WRN protects cells from DNA damage induced by the benzene metabolite hydroquinone

Xuefeng Ren*, Sophia Lim*, Martyn T. Smith and Luoping Zhang{dagger}

Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720

{dagger} Corresponding Author's Address: Luoping Zhang, School of Public Health, University of California, Berkeley, B84 Hildebrand Hall MC #7356, Berkeley, CA 94720. Phone: (510) 643-5189; FAX: (510) 642-0427; Email: luoping{at}berkeley.edu

Received September 23, 2008; revision received November 19, 2008; accepted December 3, 2008


  Abstract

Werner syndrome (WS) is a rare autosomal progeroid disorder caused by a mutation in the gene encoding the WRN protein, a member of the RecQ family of helicases with a role in maintaining genomic stability. Genetic association studies have previously suggested a link between WRN and susceptibility to benzene-induced hematotoxicity. To further explore the role of WRN in benzene-induced hematotoxicity, we used short hairpin RNA (shRNA) to silence endogenous levels of WRN in the human HL60 acute promyelocytic cell line and subsequently exposed the cells to hydroquinone. Suppression of WRN led to an accelerated cell growth rate, increased susceptibility to hydroquinone (HQ)-induced cytotoxicity and genotoxicity as measured by the COMET assay, and an enhanced DNA damage response. More specifically, loss of WRN resulted in higher levels of early apoptosis, marked by increases in relative levels of cleaved caspase-7 and cleaved poly (ADP-ribose) polymerase 1 (PARP-1), in cells treated with HQ compared to control cells. Our data suggests that WRN plays an important role in the surveillance of and protection against DNA damage induced by hydroquinone. This provides mechanistic support for the link between WRN and benzene-induced hematotoxicity.

Key Words: Werner syndrome protein (WRN); Benzene-induced hematotoxicity; DNA damage; Apoptosis and poly (ADP-ribose) polymerase 1 (PARP-1).

* These two authors made an equally significant contribution to this study.


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